1. Field of the Invention
The present invention relates to a method for improving mass transfer rates into dense fluids and, in particular, supercritical fluids. More particularly, the present invention is directed to a method for removing soluble compositions from materials. The present invention finds application in the removal of manufacture residues such as capsule mold lubricants, in the extraction of desirable material, residual solvents, and contaminants from chemical and pharmaceutical containers and preparations, and in promoting the transfer of reaction products and by-products from catalyst pores to a bulk phase thereby maintaining the activity of the catalyst and improving reaction rates.
2. Background of the Related Art
Extraction procedures are used to transfer solutes from a solid or liquid phase to a gaseous, liquid or supercritical phase. Extensive use is made of solvent extraction in industry. However, it is well known in the art that solvent extraction suffers from a number of drawbacks including environmental and health concerns associated with many solvents, residual contamination of the treated material with the solvent itself, as well as intensive/high costs often associated with conventional extraction-distillation schemes.
Extraction procedures using supercritical fluids (SCFs) rather than organic solvents have been growing in popularity. A fluid whose temperature and pressure are simultaneously higher than its critical temperature and pressure is supercritical. The surprising solubility of solids in SCFs was first noted in the late 1800""s (Hannay and Hogarth, Proc. Roy. Soc., London A29, 324 (1879)). Actual solubility of non-volatile solutes in SCFs may be as much as 106 times higher than would be calculated assuming ideal gas behavior at the same temperature and pressure.
The most ubiquitous SCF, carbon dioxide (CO2, TC=304.1 K, PC=73.8 bar), is a gas at ambient conditions. In a supercritical state, it is essentially a compressed, high density fluid at mild temperature. It is relatively innocuous, inexpensive and non-reactive under most operating conditions. Other SCFs may have higher TC and PC and may not be innocuous. Contrary to liquids, the density, solvent power or selectivity of a SCF can be easily altered with relatively small changes in pressure or by addition of small amounts of an organic solvent. The change in CO2 density (with pressure at 35xc2x0 C. determined using an equation of state developed specifically for CO2) does not increase linearly with increasing pressure. Small changes in pressure can produce large changes in density when operating close to the critical point, for instance at 83 bar where the compressibility of CO2 is high. Relatively large changes in pressure may result in relatively small changes in density when operating at higher pressures, for instance at 700 bar where CO2 compressibility is low.
Because of its gaseous nature, a SCF is also characterized by a higher diffusivity and lower interfacial tension than liquids, and has the ability to freely penetrate a matrix such as pores in a catalyst with no phase change. A SCF such as CO2 can also be vented out of an extractor, leaving no residue and no need for drying.
Numerous gases other than CO2 may be converted to SCFs at temperatures and pressures commonly employed in industry, including, without limitation, hydrocarbons (e.g. methane, ethane, propane, butane, pentane, hexane, ethylene and propylene), halogenated hydrocarbons, and inorganic compounds (e.g., ammonia, carbon dioxide, sulfur hexafluoride, hydrogen chloride, hydrogen sulfide, nitrous oxide and sulfur dioxide). SCFs have been used to extract numerous compounds including aliphatic and aromatic hydrocarbons, organic esters of inorganic acids, organosilicons and organometallics.
SCFs have found a particular niche in cleaning items. U.S. Pat. No. 5,267,455, incorporated by reference herein, discusses a number of references which disclose the use of SCFs to remove materials as diverse as oil and carbon tetrachloride residues from metals to soils from garments. SCFs have also been used as extracting agents to deasphalt lubricating oils, to obtain edible oils, and decaffeinate coffee (Zosel, U.S. Pat. No. 3,806,619).
SCFs have been reported to be useful in other extraction applications including re-dissolution of adsorbed material (U.S. Pat. No. 4,061,566), the formation of porous polymers, removal of residual solvents from articles formed by compression such as tablets (U.S. Pat. No. 5,287,632), monomer purification and fractionation of various polymers. A possible drawback of SCFs such as CO2 is that they generally have limited solvent power for many polar and high molecular weight compounds. Therefore, they are often used for material purification or selective extraction.
SCFs are also used for crystallization (See, e.g., U.S. Pat. Nos. 5,360,478 and 5,389,263) as well as micronization of solutes in organic solutions (See, e.g., U.S. Pat. No. 5,833,891). Solutes may also be micronized by rapidly expanding a SCF solution down to a pressure where the solute is no longer soluble.
Use of SCFs as reaction media includes applications for chemical deposition of a reaction product on substrates (See, e.g., U.S. Pat. No. 4,970,093), oxidation of organics in water (Modell, U.S. Pat. No. 4,338,199), and maintenance of catalyst activity (U.S. Pat. Nos. 4,721,826 and 5,725,756). For example, Tiltsher et al. (Angew. Chem. Int. Ed. Engl. 20:892,1981) report that the activity of a porous catalyst can be restored by elevating pressure or temperature to a level where the deposited coking compounds are re-dissolved in a supercritical reaction mixture. However, on a whole, catalyst reactivation and deactivation using SCFs has yet to become adopted widely in the industry possibly due to either low catalyst activity when compared to the alternate industrial processes in place, or because catalyst activity is not maintained at a reasonably high level for long enough time. Applicants have hypothesized that diffusion limitations of reactants, products, and catalyst deactivating material are still present, thereby limiting the usefulness of these techniques.
A substantial discussion of the many uses to which SCFs have been employed is set forth in the text Supercritical Fluid Extraction by Mark McHugh and Val Krukonis (Butterworth-Heinmann 1994).
While SCFs proffer many advantages over organic solvents, several investigators have noted drawbacks with conventional supercritical fluid extraction (SFE) procedures. A problem associated with SCFs is the low mass transfer rate of a solute in a confined space to a bulk supercritical phase. The rate of solute extraction depends on the solute""s dissolution rate, solubility, and rate of mass transfer into the bulk solvent phase. Despite higher diffusivity than liquids, SCFs still exhibit limited ability to rapidly transfer extracted material from confined spaces to a bulk supercritical phase. Lack of thorough mixing between the fluid in the bulk phase and the fluid in the confined space limits mass transfer to essentially the diffusion rate of the solute(s). Normally, dissolution and mass transfer rates can be enhanced by thorough mixing between a bulk phase and a solute phase as by means of an impeller; however, the degree of enhancement in mass transfer rates is limited when the solute resides in confined spaces such as micropores, interstices, nearly closed containers or closed containers where little mixing will take place. In these cases, interphase mass transfer between the fluid in the confined spaces and the fluid in the bulk phase is often a rate limiting step.
A variety of applications in the pharmaceutical, chemical and other industries suffer from problems associated with slow mixing between a fluid or fluid mixture in a confined solid space, and a fluid or fluid mixture in a bulk phase. These problems can be so severe that they can reduce the efficiency of the process, sensibly increase processing costs, or require the use of alternative, less environmentally friendly processes to overcome these limitations.
A particular problem identified in the pharmaceutical arts is the presence of soluble impurities in drug substances and delivery formulations. For example, residual amounts of organic solvents and lubricants used in formulation processes are frequently found in porous matrix formulations. Such solvents may hamper dissolution rate by filling microchannels and by making active drug inaccessible to gastrointestinal fluids.
Soluble impurities may also be found in the drug active itself. Similarly, it is known that hard gelatin capsules used to store pharmaceutical powders which are to be administered to a patient by inhalation upon puncture of the capsule often provide non-uniform release of the pharmaceutical powder. It has recently been discovered that the non-uniform release is due to lubricant and/or plasticizer compositions which are deposited on the internal surfaces of capsules during the manufacture of the capsule (the lubricants being used to permit removal of the formed capsule shell from its molding pin-special plasticizers are sometimes used to improve capsule elasticity). One group has proposed that the capsules, conventionally sold as an assembled unit, be opened and exposed to a solvent which dissolves the lubricant to prevent sticking of the drug to the capsule interior (See, U.S. Pat. No. 5,641,510). Such technique, however, may suffer from a number of drawbacks including: the requirement that the two halves of the shell be separated when extracting and drying the capsules, possible residual organic solvent contamination, and the need for drying of the capsule shells after treatment with the solvent. Methods of extraction that allow for the removal of mold lubricant from assembled capsules, as provided by the manufacturer, are more desirable than methods requiring the capsules to be disassembled prior to their extraction; however, mass transfer of lubricant from inside the capsules to the bulk solvent through the tight space between the capsule cap and capsule body is limited when using conventional methods of extraction.
The inability to extract desirable material, residual solvents, or other soluble impurities from confined solid spaces can also pose significant problems in other areas of the chemical arts.
It is well known in the chemical arts that catalytic loss of activity occurs as catalytic reactions proceed. Loss of activity is generally associated with: (1) a reduction in the number of active sites on the internal or external surface of the catalyst due primarily to poisoning of the catalyst with compounds carried over into the reaction system; (2) aging caused by structural changes of the catalytically active surface (e.g. by sintering, recrystallization and the like); (3) deposition of sparingly volatile substances on the external or internal surface of the catalyst (so-called xe2x80x9ccokingxe2x80x9d) caused by either carry over into the reaction system or undesired parallel reactions or secondary reactions in the catalyst milieu. The primary methods used for reactivating catalysts are calcination and solvent extraction. Both of these methods, however, suffer from adverse effects; for example, calcination causes deactivation of the catalyst through aging, while solvent extraction introduces foreign substances into the reaction system. Coking of acid catalysts is particularly problematic (coking is typically caused by side reactions that involve mainly acid-catalyzed polymerization and cyclization of olefins that produce higher molecular weight polynuclear compounds which undergo extensive dehydrogenation, aromatization and further polymerization). Methods for efficiently and continuously removing catalyst coking material from catalyst pores would therefore be desirable.
An interdisciplinary problem is the problem of contamination found in the interstices of objects exhibiting porous surfaces, tight clearances, or which are otherwise swellable. Removal of contamination from interstices is difficult as the contaminant is protected from external cleaning agents (such as solvents, vacuum, etc.) by the interstice itself.
U.S. Pat. No. 5,514,220 to Wetmore et al. teaches that cleaning of porous materials and materials which exhibit tight clearances between adjoining components, such as gyroscopes, accelerometers, thermal switches, nuclear valve seals, electromechanical assemblies, polymer containers, special camera lenses, laser optics components and porous ceramics, can be improved by raising or spiking the pressure of the SCF to levels at least 103 bar greater than the initial pressure of the SCF. The large pressure pulses used by Wetmore et al. result in a relative difference between the uppermost and lowermost levels of density       %    ⁢          xe2x80x83        ⁢    Δ    ⁢          xe2x80x83        ⁢    ρ    =                    (                                            ρ              high                        -                          ρ              low                                            ρ            high                          )            Thigh        *    100  
of the fluid in the range of 45% to 72%. This range is typical of those used in other pressure pulse or, alternatively pressure swing processes. Such large swings in fluid pressure and density are designed to purge a large fraction of the solute in solution out of the solid material and into the bulk phase within every period of pressure pulse. Few such pulses are therefore generally needed to complete an extraction process involving contaminants; however, such large drops in pressure can be accompanied by large drops in temperature, especially when using fluids such as CO2 which can exhibit a relatively high Joule-Thompson coefficient. Contrary to processes such as conventional pressure swing adsorption (U.S. Pat. No. 3,594,983) which involve non-supercritical, low density gases where periodic and relatively large drops in pressure and density can be effected in a relatively short period of time, such drops cannot be easily achieved with SCFs. Because of the relatively much higher density of SCFs, purging of a large fraction of fluid out of the extraction vessel will normally require a longer time. Moreover, because of the higher Joule-Thompson coefficient of such fluids as CO2, severe cooling and other processing problems will limit the ability to simultaneously rapidly drop pressure and rapidly reheat the vessel to processing temperature.
Another application of pressure pulse cleaning with SCFs is in polyethylene production where rapid, large pressure drops are used to strip off polyethylene deposited on heat transfer surfaces of the reactor (McHugh and Krukonis, 1994, p.191)). Relatively large pressure swings are similarly used to re-dissolve adsorbed substances in SCFs (U.S. Pat. No. 5,599,381), and to extract minerals and hydrocarbons from cracks in subsurface deposits (U.S. Pat. Nos. 4,163,580 and 4,059,308).
Co-pending U.S. patent application Ser. No. 09/157,267, the international counterpart of which is published as WO 99/18939, a commonly assigned application, teaches that undesirable materials, in particular capsule mold lubricant, also can be removed from within the cavity delimited by the internal surfaces of gelatin capsules using SCFs even if the capsule shell counterparts are joined with one another to form one capsular element. In this patent application, methods for treatment of capsules used to store pharmaceutical formulations (referring to a formulation containing at least one active drug and, optionally, a pharmaceutically acceptable carrier or excipient) in capsules are described. Capsules may be manufactured from numerous materials including gelatin, cellulon and modified cellulose, starch and modified starches and plastic. The drug is delivered by dry powder inhalation devices, which pierce the capsules to allow the patient to inhale the drug. A SCF such as CO2 has a special affinity for lipidic material such as lubricants used for capsule mold release, and is therefore particularly suitable for such an application. CO2 also does not alter the color, appearance or physical properties of the capsules. Reduction in the amount of lubricant in the capsule is disclosed to reduce retention of drug product in the capsule and to improve the reproducibility of the amount of drug inhaled.
While large swings in pressure/density improve extraction, such swings have been found to result in processing problems. Large pressure/density swings often result in severe cooling of the SCF and extraction vessel. The cooling problem can be especially problematic with larger vessels, and particularly with use of fluids such as CO2 which exhibit relatively high Joule-Thompson coefficients. Cooling may adversely affect endothermic reactions, produce non-uniformity in temperature within a vessel, and cause condensation or undesired precipitation of extracted material. Large pressure pulses may also induce substantial changes in fluid density, solvent power, temperature and reaction rates (reaction rates may be decreased either due to cooling or changes in SCF density). Repeated cooling and heating combined with repeated large pressure drops can lead to fatigue of the pressure vessel. As large pressure/density swings further typically require a long time to implement, catalyst deactivation may also occur. Moreover, when large pressure drops are used, extraction does not take place constantly at the pressure where solvent power is high, thereby reducing extraction efficiency.
For instance, adiabatic temperature drops for CO2 can be estimated using published data for the Joule-Thompson coefficient   μ  =            (                        δ          ⁢                      xe2x80x83                    ⁢          T                          δ          ⁢                      xe2x80x83                    ⁢          P                    )        H  
where H is the enthalpy, T is the temperature and P is the pressure, provided in Perry""s handbook Perry and Green, Perry""s Chemical Engineering Handbook, Sixth Ed., p. 3-109, 1984). It is found that at 50xc2x0 C., a drop in pressure from 101 bar to levels resulting in a change in density       %    ⁢          xe2x80x83        ⁢    Δρ    =                    (                                            ρ              high                        -                          ρ              low                                            ρ            high                          )            Thigh        *    100  
of 60% results in a drop in temperature of 18.3xc2x0 C. In this instance, the potential drop in temperature is relatively large and its may not be possible to rapidly reheat a high pressure vessel back to the temperature prevailing just prior to initiating pressure drop. Repeating such pressure swings as in pressure pulse and swing processes may eventually cause the vessel temperature to drop below the critical point and liquid CO2 may then form.
The walls of large high pressure vessels are generally thick and made out of stainless steel. Because stainless steel exhibits low thermal conductivity, it is often not heated externally, and fluids are normally preheated to processing temperature prior to entering the vessel. A large temperature drop is therefore often difficult to overcome, and a large section of the vessel close to the exit or expansion valve can become excessively cold. Materials sensitive to large swings in temperature and/or pressure can thus be especially affected. Large pressure/density swings have been seen to lead to damage, degradation or collapse of materials sensitive to repeated large changes in temperature, pressure or fluid density. Even if the materials are not sensitive to large pressure and/or temperature swings, this creates regions of non-uniformity in the vessel temperature which can result in non-uniformity in the fluid solvent power. The treated material may thus not be uniformly depleted of its soluble material, and the extraction efficiency will be non-uniform. Material containing liquid substances such as water or other polar material that freezes in the cooled region could also block access to soluble material.
Even in the absence of a temperature drop, a large change in density can have negative effects. For instance, at 40xc2x0 C., the solubility of benzoic acid drops from about 0.45% to 0.009% as the density of CO2 is reduced 60%, from 0.75 g/mL to 0.3 g/mL (McHugh and Krukonis, p.369). Such a large drop in solubility can cause the dissolved solute to precipitate.
Use of large pressure and density swings for maintenance of catalytic activity is not possible because large changes in fluid density as means of purging coking compounds could not take place fast enough to respond to the need to rapidly purge by-product material out of a catalyst matrix before it undergoes transformation into undesirable, insoluble material. Such changes could also induce large, undesirable variability in reactions rates and selectivities.
The above examples suggest that the pressure swing and pressure pulse processes, which were originally developed for non-SCF applications, are generally not suitable for applications involving fluids such as CO2, which is the SCF of choice. Prior art applications involving non-SCFs such as pressure swing adsorption could not use a pressure modulation technique with relatively small pressure and density changes because those applications required relatively large pressure and density changes to be effective.
There is a need, therefore, for a process that improves interphase mass transfer between fluids in confined spaces and SCFs in a bulk phase so as to permit efficient extraction of contaminants found in such confined places without the limitations of previous art. Preferably such extraction should take place with relatively little change in the SCF density; little cooling of the vessel; no significant change in reaction rates; little if any precipitation of extract, reactants or products; no significant shattering, collapsing or degradation of sensitive material; and minimal, if any, fatigue on the pressure vessel in which extraction is conducted. Preferably the process would operate continuously near the highest pressure where the SCF solvent power and the solute concentration in the SCF can be at their highest.
The present invention provides a process by which material inside a confined space can be solubilized and efficiently transferred to a bulk fluid phase by employing SCF solvents in an original and judicious way. The process employs repeated modulation of SCF pressure/density between an upper level and a lower level within a relatively narrow range of fluid density, coupled with an adequate frequency of modulation to remove materials. The present method permits enhanced extraction rates and improved control of the rate of removal of materials into the extracting fluid without the limitations of the previous art. Surprisingly, it is found that the present method can be more than 7-fold more efficient than conventional SFE at extracting material such as solvents or polymers from confined spaces such as closed bottles which were previously not amenable to extraction by conventional methods. More surprisingly, the method is found to be efficient at extracting material in relatively large quantities and can therefore also be used in applications involving not only extraction of contaminants as in cleaning applications but also in extraction of bulk quantities of soluble material. This is demonstrated by the novel application of SCFs to the extraction of bulk material from such substrates as containers such as bottles, drums and syringes, which are to a large extent impervious to extraction with SCFs at constant pressure and were previously not addressed by other extraction techniques such as pressure pulse and pressure swing processes. According to this invention, such material is preferably extracted using relatively small modulations in fluid pressure and density. Such unique applications in addition to the applications to catalytic reaction enhancement open broad avenues for expanding the use of SCFs.
The effectiveness of relatively small magnitude pressure modulation in enhancing mass transfer was not envisioned by previous investigators partly because it was unobvious that relatively small but repeated changes in fluid density can have appreciable effects on mass transfer. Surprisingly our experimental and modeling studies have now demonstrated that pressure modulation can be even more efficient than pressure pulse and pressure swing extraction in removing soluble material from matrices without incurring the multitude of limitations associated with the prior art. Moreover, while pressure pulse and pressure swing processes have not been reported to be of any use in enhancing catalytic reaction rates and continuous maintenance of catalyst activity, the present invention is uniquely suited for such applications.
While not wishing to be bound by any theory, it is hypothesized that the enhancements and improvements provided by the present process result from an improved convective flow of the extracted material out of the matrix every time pressure is reduced, and improved convective flow of SCF containing less solute material every time pressure is increased. Such repeated convective flow can cause mixing and turbulence within the SCF in the confined matrix, and thereby increase the rate of extraction of the material from the substrate. High frequency modulations can also possibly cause propagation of mixing effects within the confined matrix thereby also increasing the extraction efficiency. It is therefore believed that it is possible to sensibly affect the rate of extraction of compounds dissolved in a SCF phase present inside a confined matrix by effecting convective flow into and out of the matrix rather than by relying solely on mostly slow diffusive flow as a means for transfer of solute from the SCF in the matrix to the bulk SCF phase.
It has been determined that substantial convective flow can occur using relatively small pressure modulations at relatively high frequencies correlating with relatively small changes in fluid density, where the physical properties of the fluid and vessel are little affected throughout the pressure modulation phase. Taking advantage of the gas-like compressibility and diffusivity, and liquid-like solvent power of SCFs, there is provided by the present invention a means to force a bulk SCF phase into confined spaces using a relatively small pressure increase and to force a small fraction of the content of confined spaces into the bulk phase using a relatively small pressure reduction. Repeated pressure modulation provides a means to repeatedly mix the content of the solute poor bulk phase and the solute rich confined phase, thereby enhancing extraction efficiency.
It has been found that the use of relatively small pressure/density modulations at relatively higher frequency allows more flexibility in processing and can yield high extraction efficiencies without incurring the multitude of problems associated with large swings in pressure. A high extraction efficiency of extraction can be achieved through control of the magnitude and frequency of relatively small changes in pressure/density. By use of the present invention, it is possible to achieve the same or even better extraction efficiency than possible with large pressure pulses. The present invention can be extended to reaction systems involving porous catalysts. When applied to reaction systems, it is possible to overcome a variety of problems associated with catalyst coking and inadequate reaction rates.
The magnitude of modulation in fluid density determines the magnitude of fluctuations in fluid solvent power and physical properties, reaction rates and adiabatic cooling effects. Contrary to previous art, in this invention the density and physical properties of the processing fluid do not experience considerable changes during pressure modulation. The driving force for mass transfer in this invention is relatively small changes in density. Contrary to pressure pulse or pressure cleaning, the change in fluid density is always kept relatively small, and the amount of fluid removed from the matrix is therefore relatively small within any period of pressure modulation. Because changes in density are relatively small when compared to prior art, they can be effected with a relatively higher frequency and always near the uppermost density where the solvent power is highest. The ability to control and increase the frequency of density modulation can provide an opportunity to be possibly even more effective at extracting soluble material from an insoluble matrix than possible with pressure swing and pressure pulse processes.
It has been determined that pressure modulations imparting relative differences in fluid density between the uppermost level of density and the lowermost level of density of no more than about 5% can be sufficient to effect a large enhancement in extraction efficiency when compared to conventional SFE at substantially constant pressure. Depending on the characteristics of the fluid, solute, matrix to be extracted, system and process under consideration, differences in density of up to 30% can be used. A 30% relative density difference is equivalent to a fluctuation in fluid density of about xc2x115% around the average fluid density and solvent powder. It is well below relative differences routinely used in the prior art and can therefore be used with much less effect on fluid properties. For instance, it is found that at 50xc2x0 C., a drop in pressure from 101 bar to levels resulting in a relative difference in density of 5% and 30% respectively will result in adiabatic temperature drops of only 0.9xc2x0 C. and 6.8xc2x0 C. respectively. This compares to a drop of 18.3xc2x0 C. when using a change in density of 60%. The present invention is therefore also process whereby pressure is modulated without incurring large temperature drops or swings and their associated disadvantages.
This invention provides flexibility in controlling modulation frequency, extraction time as well as extraction efficiency without severely affecting fluid properties. The present invention does not induce large changes in temperature during pressure reduction, and therefore does not cause thermally sensitive material to be damaged.
One aspect of the present invention consists of a practical process for removal of material from the interior of closed or nearly closed matrices such as hard gelatin capsules, vials, bottles, syringes and drums. Under conventional processing conditions, the extraction efficiency from such matrices is often limited by slow diffusion of extracted material through restricted channels or pores of the matrix. In this aspect of the present invention, there is made use of SCFs, in a preferred embodiment CO2, in a novel way to enhance transport of extracted material from inside such matrices to a bulk supercritical phase. Advantages of using non-toxic SCFs such as CO2 in place of organic solvents include environmental friendliness. SCFs such as CO2 further provide high compressibility and diffusivity over a wide range of pressures which allow easy penetration into small interstices and passages with no phase change. Recovery of extracted material from CO2 can also be accomplished by merely expanding it to a low pressure gaseous state and allowing for the condensation or precipitation of extracted material to take place.
In one embodiment of the invention there is disclosed a method for extracting materials from a substrate comprising the steps of: (a) exposing the substrate to a SCF in which said material is substantially soluble but said substrate is not; (b) repeatedly modulating the pressure of said SCF between two or more pressure levels wherein the relative difference between the uppermost and lowermost levels of density during modulation is less than about 30%. Preferably modulation is repeated at least 5 times, more preferably in excess of 20 times, and more preferably in excess of 50 times. More preferably, the difference between the uppermost and lowermost levels of density is less than about 5%.
In another embodiment of the present invention, there is disclosed a method for extracting materials from a substrate such as porous material, microtubing, vials, syringes, bottles and drums comprising the steps of: (a) exposing the substrate to a SCF in which said one or more materials is substantially soluble but said substrate is not; (b) repeatedly modulating the density of said SCF between two or more density levels, wherein the density changes by no more than 30%. Preferably, the relative difference between the uppermost and lowermost levels of density is less than about 5%, and modulation is repeated at least 5 times, more preferably in excess of 20 times, and more preferably in excess of 50 times.
In yet another embodiment of the present invention, there is disclosed a method of treating hard gelatin, cellulose, or plastic capsules used for storing a dry, powdered pharmaceutical formulation wherein the capsule has SCF-soluble material on its internal surfaces comprising the steps of: (a) exposing the capsule to a SCF in which said SCF-soluble material is substantially soluble but in which said capsule is not; (b) repeatedly modulating the pressure of said SCF between two or more pressure levels, wherein the difference between the uppermost and lowermost levels of fluid density is less than about 30%. Preferably the relative difference between the uppermost and lowermost levels of density is less than about 5%, and modulation is repeated at least 5 times, more preferably in excess of 20 times, and more preferably in excess of 50 times.
And yet another embodiment of the present invention entails a method for maintaining the activity of catalysts whose activity can be reduced by transformation products of SCF-soluble by-products of the reaction catalyzed by the catalyst, comprising the steps of: (a) exposing the catalyst to a SCF in which said SCF-soluble product and by-products are substantially soluble but in which said catalyst and its support are not; (b) repeatedly modulating the pressure of said SCF between two or more pressure levels, wherein the relative difference between the uppermost and lowermost levels of density are not more than about 30%. Preferably the relative difference between the uppermost and lowermost levels of density is less than about 5%.